In this specification where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not an admission that the document, act or item of knowledge or any combination thereof was at the priority date, publicly available, known to the public, part of common general knowledge; or known to be relevant to an attempt to solve any problem with which this specification is concerned.
The major objective in pharmaceutical delivery is to obtain an appropriate biological effect at a desired site of action. The choice of formulation can be critical to the efficacy of a pharmaceutical since the bioactivity of a pharmaceutical will be sub-optimal if it does not possess the correct physiochemical properties to allow release from the formulation at the target site of action.
Enteral delivery involves administering the pharmaceutical via the GI tract where the pharmaceutical is absorbed and distributed via the bloodstream to the target site of action. For example, pharmaceuticals delivered orally are absorbed through the intestine.
The chemical environment of the GI tract is also important to external pharmaceutical delivery. The pharmaceutical must be in a form which is stable at the different pH of the various parts of the GI tract. If the pharmaceutical forms a non-absorbable complex or is degraded chemically or enzymatically then this will decrease absorption. The pharmaceutical must also be in solution in the GI fluids to be absorbed. Sedimentation of the pharmaceutical involves the pharmaceutical forming solid particles and thus leaving the solution. Adsorption onto luminal solid particles involves solids adsorbing the pharmaceutical; that is, removing the pharmaceutical from solution. Both sedimentation and adsorption decrease absorption of the pharmaceutical. In many cases, degradation and complexation can be circumvented, or at least minimized, by chemical or formulation approaches so that they do not present a limitation to pharmaceutical uptake.
Further, if a pharmaceutical is absorbed through the intestinal or stomach wall, it then must pass through the liver. The liver is designed to eliminate foreign compounds from the body. As a result, a significant proportion of the pharmaceutical (for example, 40-50%) may be metabolised and excreted before its reaches the bloodstream. It is possible to reduce the effect of the liver on enteral administration by having the pharmaceutical absorbed through the lining of the mouth (bucchal/sublingual) or the lining of the rectum (suppositories), however these routes are not always appropriate.
Attempts to improve the bioavailability of enterally administered pharmaceuticals involve either the formation of prodrugs, for example morphine sulphate or the use of excipients which improve absorption.
Topical delivery involves administering the pharmaceutical to a membrane of the body where the pharmaceutical is absorbed and distributed. For example, pharmaceuticals delivered transdermally are absorbed through the skin.
The skin is the largest organ of the body, which functions to protect the internal organs from external chemical, physical and pathological hazards. Normal skin is divided into three layers: the epidermis, the dermis, and subcutaneous tissue. The outer cornified layer of the epidermis, the stratum corneum, possesses properties of strength, flexibility, high electrical impedance and dryness that retards penetration and proliferation of micro-organisms. The stratum corneum is also the principle barrier to transdermal pharmaceutical absorption. There is a layer of sebum protecting the skin which is considered to be a barrier to all aqueous based pharmaceutical formulations.
When travelling through the skin, a diffusing pharmaceutical molecule has three potential routes of entry to the deeper skin layers: the intercellular route, the transcellular route, and the transappendageal route. While shunt diffusion of electrolytes and large molecules through appendages may be significant, the relatively small area available for transport (0.1% of skin surface) means this route has a negligible contribution to steady state pharmaceutical flux. The main route for the permeation of the majority of molecules is commonly believed to be the intercellular route, and hence many enhancing techniques are aimed at disrupting the strong “brick and mortar” construction of the strata corneum. Current theories regarding the transport route point to two possible mechanisms: (i) passive transcellular and (ii) intracellular epidermal transport.
Pharmaceuticals are topically applied to the skin in a number of ways including ointments, patches, solutions, subcutaneous depots, poultices, plasters and transdermal delivery devices.
Interest in transdermal pharmaceutical delivery may be increasing but some fundamental limitations restrict broader application of the technology. The main limitation to the use of transdermal delivery is the rate of transport of the pharmaceutical through the skin.
Not every pharmaceutical can be administered transdermally at a rate sufficiently high enough to achieve blood levels that are therapeutically beneficial for systemic medication. Pharmaceuticals with similar molecular weights and sizes for example may absorb across the skin at different rates. Fentanyl for example permeates the skin at 2 mg/cm2/hr compared to ephedrine at 200 mg/cm2/hr. The large size of a transdermal delivery system required for fentanyl would therefore be neither practical nor economical despite the advantages of the administration route.
Skin enhancers and various formulation techniques have been developed to improve pharmaceutical absorption through the skin. Skin enhancers can include compounds like capric acid, oleic acid, azone, decylmethyl sulfoxide and hydroxy cinnamates that typically function to modify structure especially of the stratum corneum by dissolving the lipid matrix to improve permeability of pharmaceuticals. Dermal absorption of progesterone for example increases by 143% when the stratum corneum is delipidized. The enhancement increases to 843% when the stratum corneum is totally eliminated. With such aggressive modification, commonly reported problems with repeated use of such systems are therefore evident, including contact dermatitis, reddening of the skin, itching and burning that requires movement of the patch, or application of the pharmaceutical, around the body to prevent local irritation. The reddening is said to disappear within hours of removing the patch. But concern has been raised with respect to long term risk and safety with use of this type of transdermal delivery systems, mainly because increased pharmaceutical permeability is achieved at the cost of damaging a fundamentally important protective layer of the skin.
There is a need for formulations which further improve the bioavailability of biologically active compounds.